One of the guiding objectives of modern schizophrenia research is to build a bridge from molecular and cellular biology to the clinical symptoms of this psychotic mental disorder. Monoaminergic neurotransmitters have been the principal focus of schizophrenia research for many decades. Several approaches have also linked the neurotransmitter glutamate to the neurochemical alterations in patients with schizophrenia. Notably, clozapine and other atypical antipsychotics have high affinity for serotonin 5-HT2A receptors (2AR), and metabotropic glutamate receptors 2/3 (mGluR2/3) agonists have recently shown efficacy in treating schizophrenia. We identify a novel and unexpected functional brain 2AR/mGluR2 receptor complex that may unify the anti- serotonin and glutamatergic therapies of schizophrenia. Our results based on in vitro, animal models and postmortem human brain of schizophrenic subjects suggest that this 2AR/mGluR2 complex may be responsible for some psychotic symptoms in schizophrenia, and that it is the direct target of these two different classes of antipsychotic drugs. In order to understand the role of the 2AR/mGluR2 complex in brain function and to set the stage for future drug development we will pursue two aims. We will use in vitro studies in conjunction with cutting-edge computational approaches to investigate the molecular determinants at the interaction interface responsible for 2AR/mGluR2 complex stabilization and functional crosstalk. In cortical primary cultures and in vivo in mouse models we will study the neuronal signaling and behavior dependent on 2AR/mGluR2 complex function. Results of the proposed studies have the potential to provide a greater understanding of the structure and function of the 2AR/mGluR2 complex than is currently available for any G protein-coupled receptor heterocomplex, and may provide the basis for new pharmacological approaches to the treatment of schizophrenia. PUBLIC HEALTH RELEVANCE: Schizophrenia is a chronic, debilitating psychotic mental disorder that affects about one percent of the population in the U.S.A., and the seventh most costly medical illness to our society. We have discovered a new neuroreceptor complex that induces hallucinations in mouse, and is affected in schizophrenia brain. The characterization of the structure of the neuroreceptor will extend our understanding of the molecular basis of psychosis, and may provide a route to the development of new, more effective drugs for the treatment of schizophrenia.